The possibility that the cyclic nucleotides, cyclic AMP and cyclic GMP, may mediate the generation of the slow synaptic potentials was investigated in sympathetic ganglia of the bullfrog, using the sucrose gap technique. The administration or cyclic GMP, cyclic AMP, and their derivatives had no significant effect on membrane potential. The administration of theophylline (5 mM), an inhibitor of phosphodiesterase - the catabolic enzyme for cyclic nucleotides, produced a depolarization of the membrane and an increase in membrane conductance. The muscarinic slow IPSP and the hyperpolarization produced by the administration of methacholine were potentiated by theophylline. The muscarinic slow EPSP and the depolarization produced by the administration of methacholine were reduced by theophylline. The noncholinergic late-slow EPSP was reduced by theophylline. In calcium-free Ringer, theophylline greatly enhanced the methacholine hyperpolarization; in addition, the methacholine depolarization was virtually abolished. These results raise the question of whether the cyclic nucleotides may have a functional role other than generation of slow postsynaptic potentials.